Process for the manufacture of prednisolone-acetate



PROCESS FOR THE MANUFACTURE OF PREDNISOLONE-ACETATE Josef Reinertshofer, Bad Soden (Taunus), and Manfred Schorr and Rudolf Junk, both of Frankfurt am Main, Germany, assignors to Farbwerke Hoechst Aktiengesellschaft vorrnals Meister Lucius & Bruning, Frankfurt am Main, Germany No Drawing. Application August 19, 1958 Serial No. 755,889

Claims priority, application Germany August 21, 1957 13 Claims. (Cl. 260397.45)

or 3-ketosteroids (cf. U.S. Patents 2,756,179 and 2,776,-

927, Belgian Patents 544,631, 546,636 and 544,993).

All these microbiological processes require large quantities of liquids, the so-called liquid culutre media, and

above all sterile working conditions; a chemical process United States Patent would, therefore, be of great interest for the technique concerned.

Now it is well known that A -3-ketosteroids can be obtained also by chemical methods of preparation. Thus, for example, the treatment of 2,4-dibromocholestanone with collidine yields the A -cholesta-dienone-(3) (cf. Butenandt et al., B. 72, (1939), page 1617; lnhoffen et al., B. 73 (1940), page 451); 2-iodo-A -ketosteroids can be converted by means of Raney-nickel into A -ketosteroids (cf. British Patent 761,351).

Starting substances for the synthesis of prednisoloneacetate are above all the A -pregnene-l1fi,17a,2l-triol- 3,20-dione, its corresponding ll-keto derivatives and the corresponding ZI-acetates. The above mentioned chemical processes require, therefore, at least two stages of operation. It is further known that by treating A pregnene-Zl-0l-3,20-dione-acetate (desoxy-corticosteroneacetate) with lead tetra-acetate in a single-stage process a small amount of A -pregnadiene21-ol-3,20-dioneacetate (6.5%) can be obtained.

Finally, A -pregnene-l 1 8, l7a,2l-triol-3,20-dione-21-acetate (Kendalls compound F, hereinafter referred to as F-acetate) can be dehydrogenated by means of selenium dioxide to form with good yield prednisolone-acetate (cf. Belgian Patent 548,288). It is, however, also known that the. prednisolone-acetate prepared according to this method contains selenium. The separation of the selenium-containing substance is very difficult and entails a considerable reduction in the yield of prednisolone-acetate (cf. .Florey, Restivo, J. Org. Chem. 22 (1957), page 406).

Now we have found that prednisolone-acetate can be prepared from the F-acetate in a single-stage process by dehydrogenating, in a liquid phase, the F-acetate with derivatives of the trivalent thallium.

As liquid phase there are used preferably low molecular fatty acids with the exception of formic acid, e.g. acetic acid, propionic acid or butyric acid. There can, however, also be used tertiary alcohol or a mixture of tertiary butyl-alcohol with the aforementioned fatty acids, or

even a mixture of said fatty acids with inert solvents such as. benzene, toluene or xylene.

The temperature at which the process is carried out has an influence on the yield. At higher temperatures, f9;

example at 95 C., there is obtained after 3 hours, for example, in glacial acetic acid a mixture containing 20% of prednisolone-acetate and 34% of F-acetate. At 40 C. there is obtained after 500 hours, for example, in glacial acetic acid a mixture containing 33% of prednisolone-acetate and 32% of F-acetate. Prolonged action of the thallium-III-compound shifts the ratio of yield in favour of the perdnisolone-acetate, but reduces the yield of prednisolone-acetate with reference to the quantity of starting material used. When adding tertiary butanol or aromatic hydrocarbons, the reaction can be carried out at higher temperatures, for example at 80-100 C., without rapid decomposition-as is the case when using pure fatty acids. The thallium derivative used in the process of this invention is recovered in the form of the thallium- I-chloride, in a practically quantitative yield, which can be again regenerated in known manner to form the desired thallium-Ill-compound.

.The reaction of the present invention was unexpected for those skilled in the art. Up to now, no case of oxidation or dehydrogenation by means of thallium-lII-compounds was known, chiefly because such complicated molecules as those of the A -3-ketosteroids offer a great many possibilities of oxidation or dehydrogenation which, in general, aremore likely to occur than a A -dehydro genation. Thus, for; example, it is known from microbiological processes that there may occur not only a dehydrogenation of A -3-ketosteroids in l-position but, for example, also an oxidation at the carbon atoms 11 or 14 (cf. e.g. Belgian Patent 549,221); with chloranil there are formed A or A -3-ketosteroids but not A 3-ketosteroids (Agnello, Laubach, Am. Soc. 79, (1957), page 1258); with copper-acetate and oxygen the 21-hydroxyl group is oxidized (German patent application 1,002,756 laid open to public inspection) and with chromic acidtertiary butylester in pyridine the ll-hydroxyl group.

The reaction according to the present invention is preferably carried out in such a manner that the F-acetate and the thallium-III-compound in a liquid phase I are stored for a suitable period of time at temperatures rangingfrom 20-110 C., preferably from 40-80? C., the liquid phase is then removed, the residue is treated witht a convenient solvent, for example, methylene chloride, and water, and sodium bisulfite and a soluble chloride, as e.g. common salt, are added in order to reduce unreacted portions of the thallium-III-compound or to precipitate the thallium-I-chloride, respectively. The methylene chloride solution is separated dried, e.g. with sodium sulfate, and the solvent removed.

The residue, which contains besides prednisolone-acetate also decomposition products and possibly also F- acetate is worked up in known manner. It can, e.g. be triturated with a small amount of acetic ester, whereupon the prednisolone-acetate and the possibly present F-acetate are left behind in an undissolved state. The separation of the prednisolone-acetate from the F-acetate can be carried out in known manner, e.g. by countercurrent dispersion between, e.g. propylene glycol and toluene, or by paperchromatography.

As thallium-III-compound there is preferably used thallium-oxyhydrate T 1001-1 or one of the thallium 'salts of low molecular fatty acids with the exception of formic acid. On the other hand, there can also be used thallium- III-chloride while taking up the hydrogen chloride that is formed during the reaction by addition of buffer substance, e.g. sodium acetate. The thallium compound is preferably applied in excess, an excess of at least operation under sterile working conditions is unneces- I sary.

Moreover, the yields obtained by the process of the f present invention are much greater than thoseobtained f by the aforementioned process with lead tetra-acetate. In comparison to the process of dehydrogenation with selenium dioxide, the new process has furthermore the f very important advantage that already the crude product is free from inorganic impurities.

The following examples serve to illustrate the inven tron but they are not intended to limit it thereto: EXAMPLES The following table gives further examples of execu- E MPLE 1 tion which can be carried out while using the values given 400 milligrams of F-acetate and 600 milligrams of therein. thalllum llI-acetate are dissolved in 90 milliliters of gla- 15 Thus, each time a mixture of 400 milligrams of F- c1al acetic acid The solution is stored for 6 days at acetate and of Amilligrams ofthe thallium-III-compound 50 C., 600 milligrams of thallium-III -acetate are then is heated in L for a period t to a temperature of T C. added gain and the wholeis stored again for a further 6 and worked up in the manner as described in Example 1. days at 50 C. The glacial acetic acid is then decanted The so obtained crude product has a content of x% of under reduced pressure at 50 C., the residue is shaken prednisolone-acetate and y% of F-acetate.

Example A mg. Thallium-III- L t '1, C a: y

compound 7 days; 50 14 54 5.5 days--- 50 22 56 11 dayq..- 50 20 4 hours 95 13 39 24 hours 60 18 64 110 hours 50 31 '48 184 hours" 50 32 20 21 day's 40 21 34 21 days-.- 40 33 32 800 2 of gla l ace a 24hours..- 70 17 -46 100 m1. tert. butanol. :800 do 50 m1. of glacial acetic acid and 12 hours..- 80 4 40 50 ml. of toluene. 400 Oxyhydrate 80 ml. of propionic acid 24 hours"- 70 10 50 400 .do 80 ml. of butyric acid 24 hours '70 4 4 30 with 100 milliliters of methylene chloride and 10 milliliters of a saturated solution of common salt to which has been added such a quantity of sodium bisulfite as is left on the point of a spatula. Thereupon two layers form while the brown colour of the trivalent thallium disappears, and thallium-I-chloride separates at the separation planeof the two phases of liquids, which is collected by filtration. The methylene chloride phaseis thenseparated 'oif, dried with sodium sulfate and the. solvent evaporated. There remain behind 390 milligrams of a substance having a paper-chromatographically deter mined content of 32% of prednisolone-acetate and 36% of F-acetate (determination according to Zafiaroni et al., J. biol. Chemistry, 188, (1951), page 763).

The crude product is then triturated with a small amount of acetic ester and filtered with suction in the cold. The remaining product has a content of of prednisolone-acetate and of F-acetate. By preparative descending chromatography with the aid of Schleicher & Schiill paper 2043 b Mgl and propylene glycol as stationary phase and toluene as mobile phase there are obtained on a paper having 50 cm. of length two sharply separated fractions the first of which contains the unreacted F-acetate and the second containing prednisolone-acetate. After evaporation of the solvent and trituration with a small amount of acetic ester in order to eliminate thepropylene glycol there is obtained pure prednisolone-acetate.

A sample of this substance yields, after being recrystallized from methanol, a product having a spectrum which shows all the infrared absorption peaks typical for this substance (at 6.02; 6.20; 6.26; 7.62; 8.55; 10.66; 12.16 and in which all the peaks which. are typical for the F-acetate are missing (at 6.12; 6.88; 10.16; 11.36; 13.4112).

EXAMPLE 2 A mixture of 400 milligrams of F-acetate and 400 milligrams of thallium oxyhydrate is heated for 3 honrs on pound of the group consisting of thallium oxyhydrate and thallium (III) salts of fatty acids containing from two to four carbon atoms in a liquid phase and at atemperature between about 20 and 110 C., said liquid phase being a member of the group consisting of acetic, propionicand butyric acids, mixtures of said acids with tertiary butyl alcohol, and mixtures of said acids with an inert solvent of the group consisting of benzene, toluene and xylene.

2.A process as defined in claim 1 wherein the temperature is between about 40 and C.

3. A process as defined in claim 1 wherein the tallium compound is thallium oxyhydrate.

4. A process as defined in claim 1 wherein the thallium compound is thallic acetate.

5. A process as defined in claim 1 wherein theliquid phase is glacial acetic acid. 7

6. A process as defined in claim 1 wherein the liquid phase is propionic acid.

7. A process as defined in claim 1 wherein theliquid phase is butyric acid. a V

8. A process as defined in claim 1 wherein the liquid phase is a mixture of glacial acetic acid and tertiary butanol.

9. A process as defined in claim 1 wherein the liquid phase is a mixture of glacial acetic acid and toluene.

10. A process for preparing prednisolone-acetate which comprises dehydrogenating A -pregnene-llfi,17a,21-triol- 3,20-dione acetate-(21) (F-acetate) with a solution of thallic acetate in glacial acetic acid for about twelve days at a temperature of about 50 C., the ratio by weight of F-acetate to thallic acetate being about 1:3; distilling the methylene chloride solution with acetic acid ethyl ester; and separating the remaining mixture of prednisolone-acetate and F-acetate.

11. A process for preparing prednisolone-acetate which comprises dehydrogenating A -pregnene-11,8,17a,21-triol- 3,20-dione acetate-(21) (F-acetate) with a solution of thallio acetate in a 1:1 mixture of glacial acetic acid and toluene for about twelve hours at a temperature of about 80 C., the ratio by weight of F-acetate to thallic acetate being about 1:2, distilling off the liquid phase; treating the residue with methylene chloride and an aqueous solution of sodium bisulfite; washing the product obtained from the methylene chloride solution with acetic acid ethyl ester; and separating the remaining mixture of prednisolone-acetate and F-acetate.

12. A process for preparing prednisolone-acetate which comprises dehydrogenating M-pregnene-llfl,l7m,2l-triol- 3,20-dione acetate-(21) (F-acetate) with a solution of thallic acetate in a 1:5 mixture of glacial acetic acid and tertiary butanol for about 24 hours at a temperature of about 70 C., the ratio by weight of F-acetate to thallic acetate being about 1:2 distilling off the liquid phase; treating the residue with methylene chloride and an aqueous solution of sodium bisulfite; washing the product obtained from the methylene chloride solution with acetic acid ethyl ester; and separating the remaining mixture of prednisolone-acetate and F-a-cetate.

13. A process for preparing prednisolone-acetate which comprises dehydro-genating A -pregnene-l1;3,l7u,21-triol- 3,20-dione acetate-(21) (F-acetate) with a solution of thallic acetate in propionic acid for about 24 hours at a temperature of about 70 C., the ratio by weight of F-acetate to thallic acetate being about 1:1; distilling the propionic acid 01f at about 50 C.; treating the residue with methylene chloride and an aqueous solution of sodium bisulfite; washing the product obtained from the methylene chloride solution with acetic acid ethyl ester; and separating the remaining mixture of prednisoloneacetate and F-acetate.

No references cited. 

1. A PROCESS FOR PREPARING PREDNISOLENE-ACETATE WHICH COMPRISES DEHYDROGENATING $4-PREGNENE-11B,17A,21-TRIOL3,20-DIONE ECETATE-(21) WITH A TRIVALENT THALLIUM COMPOUND OF THE GROUP CONSISTING OF THALLIUM OXYHDRATE AND THALLIUM (III) SALTS OF FATTY ACIDS CONTAINING FROM TWO TO FOUR CARBON ATOMS IN A LIQUID PHASE AND AT A TEMPERATURE BETWEEN ABOUT 20 AND 110*C., SAID LIQUID PHASE BEING A MEMBER OF THE GROUP CONSISTING OF ACETIC, PROPIONIC AND BUTYRIC ACIDS, MIXTURES OF SAID ACIDS WITH TERTIARY BUTYL ALCOHOL, AND MIXTURES OF SAID ACIDS WITH AN INERT SOLVENT OF THE GROUP CONSISTING OF BENZENE, TOLUENE AND ZYLENE. 